Block 3 EXAM Flashcards
TAG synthesis in adipose tissue
Point mutations (Single base or base pair mutation that can be artificially induced)
Silent
Nonsense
Missense
Frameshift
Silent = Doesn’t fuck with AA production or protein function
Nonsense = Fucks with translation pre-maturely by changing codons to STOP codons (UAA, UAG, UGA) in the mRNA making truncated polypeptides
Missense = A single base pair sub that changes the codon entirely, making it code for another AA (changes protein function ** like in sickle cell glutamic-acid –> valine)
Frameshift = An insertion or deletion that’s NOT a multiple of 3, either causing a STOP or diff AA
* Insertion (adds nucleotides & changes the
coding sequence)
* Deletion (removes nucleotides to shift the
reading frame of mRNA and fuck
translation)
Insertion & Deletion
Happens in multiples of 3 to add/remove entire AAs
- large deletions = partial or whole gene deletion
Caused by unequal cross-over
Retrotransposons (can’t be artificially caused)
Mobile elements that use mRNA to get copied into DNA and get inserted into a new spot in the genome.
- SINEs (short interspersed nuclear elements)
- LINEs (long interspersed nuclear elements)
* L1 elements have internal promoters
(recognized via RNA pol II), 2 open reading
frames (ORFs 1 =encodes nucleic acid-binding protein 2= endonuclease & reverse transcriptase activities), & A short target site for
duplication
These mess with coding sequences and switch genes off
Transposition of L1
RNA pol II transcribes L1 element into L1 RNA & it gets polyadenylated in the nucleus
—> L1 RNA moves to the cytoplasm & gets translated into ORF1 (nucleic acid-binding protein) + ORF2 (multimeric protein)
—> L1 RNA+ORFS1/2 move back to the nucleus & bind chromosomal DNA
—> Endonuclease cuts the DNA molecule & a reverse transcriptase uses L1 RNA to make an ssDNA (the 3’ of chromosomal DNA acts like a primer for this)
—> the new L1 inserted DNA moves into the chromosomal DNA to replace the cut sequence & L1 RNA is trashed
—> the opposite strand of DNA is cut to make room for a second strand of L1 complementary DNA
—> finally, a ligase glues the new pieces together
Dynamic mutations
When a repeated sequence of trinucleotides/tetranucleotides gets more unstable, the bigger it gets via mitosis/meiosis
(CCG)n = FRAXA mental retardation
(CAG)n = Chorea Huntington, Spinal-bulbar
muscular atrophy, spinocerebellar ataxia
1, & other neurological disease
(GAA)n = Friedreich ataxia
(CCTG)n = Myotonic dystrophy
(CGG)n = FRAXE mental retardation disorders
Diseases associated with Retrotransposons & Insertions
Type 1 neurofibromatosis
Duchenne muscular dystrophy
B-thalassemia, hemophilia A+B
Familial boobie/bootyhole cancer
Huntington Disease
Disorder type
Genetic Cause
Causes
New Apparent Case cause
Carrier & Areas of Impact
Symptoms
Type = Auto DOM
GC=
- A dynamic mutation in HD gene on X.4p
Causes=
- 10-26, CAG repeats in exon 1, encoding an abnormal huntingtin protein with 36 polyglutamine residues (loss-of-function)
- The expanded CAG repeats happen when the DNA pol slips
Carrier = usually the daddy
Areas of impact =
- Neuropathy (atrophy)
* in the neostriatum (caudate nucleus &
putamen)
*globus pallidus, thalamus, substantia nigra
& cerebellum
- Selective neuronal loss
- Astrogliosis
Symptoms =
- Progressive motor, cognitive, & mental abnormalities
- Chorea (involuntary non-repetitive jerking movement)
- Personality changes, affective psychosis, & schizo (early on)
Friedrich ataxia
Disorder type
Genetic Cause
Causes
Symptoms
DT = Auto REC
GC =
- A dynamic mutation on the FXN gene at X-9q (normally encodes frataxin, a mitochondrial protein)
Causes=
- GAA repeats in introns of FXN
Symptoms = Onset in 10-15yrs
- Gradual loss of strength & sensation
(arms/legs)
- Muscle stiffness (spasticity)
- Hypertrophic cardiomyopathy
- Impaired speech, hearing, & vision
Fragile X syndrome
Disorder type
Genetic Cause
Causes
Symptoms
DT= X-linked DOM
GC =
- A mutated FMR1 gene on Xq27.3 (normally makes a protein chaperone)
Causes=
- Repeated (CGG)n in the 5’ untranslated region of the gene (5’UTR more than 200 repeats)
Symptoms =
- Intellectual disabilities (moderate in males & mild in females)
- long narrow faces, prominent jaw/forehead, & big ears
- enlarged testes (macroochidism) & flat feet in males
- behavioural issues (hyperactivity, temper, poor eye contact, & autistic features
Splicing mutations (non-coding regions)
Genetic Cause
Sites of mutation
GC = Changed splice sites that interfere with intron excision (i.e exons are accidentally cut out or introns are kept)
Sites =
5’ GU splice site
3’ AG splice site
Cryptic splice site (spots near the 5’ & 3’ that cause partial/whole deletion of exons
Promoter mutation (non-coding mutation)
Causes
Reduces RNA pol’s affinity for promoter sites causing less production & more failed transcription of mRNA meaning there’s less protein being produced
Regulatory Element Mutations (non-coding region)
Causes
Can fuck the gene’s ability to be regulated
5’-UTR/3’UTR Mutations
Causes
Changes the mRNA’s ability to get translated by altering its stability
Beta-Thalassemia (coding & non-coding region mutation)
Genetic Cause
Causes
Effects of Different Mutation Sites
GC =
Point mutations, insertions, & base pair deletions happen in the coding & non-coding regions altering:
- B-globin genes
- 5’ Capping sequence
- 5’ Promoter region
- 3’ Polyadenylation
Causes = Produces either reduced (B+) or absent (B0) B-globin chains
Effects of different mutation sites=
–> Mutated B-globin promoter region causes reduced transcription of its mRNA
–> Mutations of 5’GT/3’AG nucleotides of introns OR donor/acceptor sequences cause fucked up splicing to make abnormal lengthened B-globin mRNA’s
–> Mutated 3’ UTR (untranslated region) of the B-globin gene means the cleavage & polyadenylation signal is lost
–> Mutations in the 5’ & 3’ DNA involved in capping & polyadenylation cause abnormal processing & transportation of B-globin mRNA to the cytoplasm (reduced translation)
–> Insertions, deletions, & point mutations can cause nonsense or STOP codons that end translation of B-globin mRNA early
cystic Fibrosis
Effects of Different Mutation Sites
EDMS=
–> Due to a 3bp deletion in the CFTR gene (Phe508del)
–> Nonsense mutation by subbing a glycine for a STOP codon at AA542
& Subbing guanine with thymine at nt1624
–> Missense mutation by subbing glycine with aspartic acid at AA551
& Subbing guanine with adenine
–> Frameshift mutation of a single nucleotide intention of thymine after the 3773rd nucleotide
OR
Frameshift mutation due to a 22bp deletion starting at the 720th nucleotide
–> Silent mutation leaving an unaltered AA (gGlu at AA 528 & guanine or adenine at 1584th nucleotide)
–> 2 splice mutations: 1 nucleotide at the 5’ junction of interferon starting after the 489th nucleotide
&
1 nucleotide from the 3’ splice junction of intron ending before the 1585th nucleotide
Loss of function VS Gain of function
LOF = Mutation stops the gene from working
-Reduced activity (hypomorph) or complete loss (amorph) of a product (typically protein)
These involve enzymes that are usually inherited via autosomal recessive or X-linked recessive manner
GOF = Mutation causes the gene to have more or a new/different function
-Increased levels of gene expression or new functions via a new product (protein) i.e
These are dominantly inherited & have a severe phenotype
Genetic polymorphism
The difference in DNA among individuals, groups or populations that come from:
- SNPs (single nucleotide polymorphisms)
- Insertion-Deletion Polymorphisms (Indel)
*Simple
*STR (Short-Tandem Repeats)
*VNTRS (Variable Number Tandem repeats)
*Retrotransposons
- Inversion polymorphism
- CNPs (Copy number polymorphisms)
SNPs (Single nucleotide polymorphism)
Locus
Locations
Locus =
usually, 2 alleles (biallelic) that correspond to 2 different bases at the same location in the genome
Locations=
- Non-coding introns
- Genes & functional elements
* may alter AA, add a STOP, or alter splice site
Indel (Insertion-Deletion polymorphisms)
Caused by insertions or deletions of base pairs, they are:
- Biallelic (simple indels with 2 alleles)
- Multiallelic
(micro & mini-satellite polymorphisms which have high mutation rates that can happen via unequal cross-over during meiosis OR DNA, polymerase, or strand slippage during mitosis)
Inversion polymorphism
A varying seized DNA sequence that inverts and makes dual orientation in the genomes of different individuals
EX.
Allele1 = ABCDEFG
Allele2 = ABEDCFG
Protein polymorphism
(products of polymorphic alleles)
ABO & Rh systems
ABO blood transfusions
Rh genes, associated diseases, & blood transfusions
These cause the different phenotypes of the mutated alleles
Ex.
- ABO & Rh blood groups (X.9)
*I^A allele = Type A (A antigen on RBC)
*I^B allele = Type B (B antigen on RBC)
*I^AB = both antigens
*2 I^O = NO antigens
*I^A or B +I^O =Type A & B respectively
A & B alleles (cause AA changes that affect glycosyltransferase specificity, hence RBC antigens)
O allele (have a single bp deletion causing a frameshift mutation that stops glycosyltransferase in homozygous persons)
Blood Transfusions =
Type A:
Antigens = A
Antibody = B
Good blood = A or O
Bad blood = AB or B
Type B:
Antigens = B
Antibody = A
Good blood = B or O
Bad blood = AB or A
Type AB:
Antigens = AB
Antibody = none
Good blood = all
Type O:
Antigens = none
Antibody = AB
Good blood = O
Bad blood = AB
Universal donor
Rh system =
Only RBCs & help maintain their membrane
Genetic cause =
- Rh locus on X.1 has 2 genes, RHD (D antigen, immunogenic ) & RHCE (C/c + E/e antigens)
* Rh complex is a tetramer with
1 RhAG (Rh-associated glycoprotein) =
directs antigens to the membrane
&
2 Rh proteins
Rh types= R D+ & rD-
- Dce (RO)
- dce (r)
- DCe (R1)
- dCe (r’)
- DcE (R2)
- dcE (r’’)
- DCE (RZ)
- dCE (ry)
Associated disease = Newborn hemolytic anemia
Blood Transfusions=
D-neg Rh blood + D-pos Rh(Dce haplotype)
= Immune resp
Common gene cases:
- Whites = RHD deletion
- RhD- in Blacks (RHD deletion, RHD pseudogene,
RHD hybrid gene)
Protein polymorphism
(products of polymorphic alleles)
ABO/Rh blood groups
&
MHC system
Inheritance:
Dominant
Recessive
Incomplete penetrance
Expressivity
Genetic Heterogeneity
Dominant = The allele that always shows phenotypes (whether it’s DD or Dd)
Recessive = The allele that only shows phenotype when its homo-recessive (dd)
Penetrance = The probability a gene will show phenotype (incomplete = reduced)
Expressivity = The severity of the gene’s phenotype
Genetic Heterogeneity = Varied mutation & disease phenotypes due to:
* Allelic Heterogeneity (When different
mutations can happen on the same locus
(ex. cystic fibrosis))
* Locus Heterogeneity (Mutations at
different loci i.e Retinitis pigmentosa)
* Phenotypic Heterogeneity (diff mutations
in the same gene cause very diff
phenotypes, i.e. RET gene mutation can
cause Hirschsprung disease or Multiple
Endocrine Neoplasia type 2A & 2B)
Autosomal VS X-linked inheritance
Auto = autosome
X = Sex chromosome
Genotypes
Homozygote
Heterozygote
Compount Heterozygote
Homo = 2 same alleles
Hetero = 2 different alleles
Compound hetero = 2 different mutant alleles
Two principles of mendelian inheritance (meiosis)
Segregation
Independent assortment
Seg = Individual diploids have two alleles for any specific trait, which separate & go into each gamete (Anaphase I)
Ind. ass = Genes at different loci are transmitted independently (Telophase I)
Mendel’s Law of Segregation
2 copies of genes segregate during transmission from parent to offspring
&
2 genes will randomly assort during haploid formation
Pleiotrophy
When 1 gene has multiple traits
Ex. Gene = PKU, Sickle-cell, & CFTR disorders
Punett Square terms
Probability
Risk recurrence prob
Multiplication & Addition rules
Probability = Likelihood of an event
Risk recurrence prob = likelihood that future kids of the affected parents will be affected
Multiplication = TWO INDEPENDENT EVENTS
the probability of 2 or more independent events happening together by multiplying their independent probabilities
EX. if the probability of a couple having a girl is 1/2, and they want 3 kids, it (1/21/21/2) = 1/8 chance
If they already have 2 kids, it’s just 1/2 chance then (cause past events won’t affect it)
&
Addition rules= ONE EVENT OR ANOTHER
The probability that any 1 of 2 or more mutually exclusive events can happen is by adding the probabilities of those events (Noting that one event will exclude the chance of the overs)
EX. A couple wants 3 kids but wants them to be diff sexes (1 girl, 2 boys vice versa). Their chances of getting either of those outcomes are 1/8+1/8 = 1/4
Autosomal inheritance
Autosomal dominant
Incomplete dominant
Traits
Ass. condition
AUTO DOM= Always phenotype (DD or Db) only affects 3/4
Incomplete DOM = 1/4 DD, 2/4 Dd, 1/4dd
Traits=
Both have an equal frequency in sexes & don’t skip generations (except in new mutations or reduced penetrance)
*Achondroplasia (Dwarfism)
Type
Caused by
Causes
Mutation Heterogeneity
Type = Auto DOM
Caused by =
- A mutated FGFR3
Causes = Gain of function (Dwarfism)
Mutation Heterogeneity =
- G1138A mutation changes Guanine to adenine -
(most common)
- G1138C Guanine to cysteine (less common)
- Familial hypercholesterolemia (FH)
Type
Caused by
Causes
Hetero VS Homo symtoms
Type = Auto DOM + Incomplete DOM
- Hetero & Homo
Caused by =
- A mutation on the short arm X.19
Causes=
- A loss of function in LDL receptor (homo & hetero mutations both decrease LDLR efficiency) that ultimately leads to Atherosclerosis
Symptoms = Hetero vs. Homo
- Hetero (have a lower number of LDLRs on liver cells, so it’s LESS severe)
* Personal or family history of Pre-coronary
artery disease
* Hypercholesterolemia
* High LDLc (under 20yrs ~200mg/dL & over
20yrs ~290-300mg/dL)
* NO coronary symptoms
* Rarely xanthomas or corneal arcus - Homo (have a higher number of LDLRs on liver cells, so it’s MORE severe & appears early)
* Tendon xanthomas
* Corneal arcus
* Ischemic heart disease
* Cerebrovascular disease
* Aortic stenosis
* Death by 30yrs
Neurofibromatosis 1
Type
Caused by
Causes
Symptoms
Mutation Heterogeneity
Type = Auto DOM (most common)
Caused by = A mutated NF1 gene (neurofibromin) on X.17q
Causes =
- It fucks with the Ras GTPase that controls cell proliferation & tumour suppression
Symptoms = prenatal to late childhood
- Cafe au lait spots
- Cutaneous neurofibromas
- Lisch nodules (iris hamartomas)
Mutant Allelic Heterogeneity=
- Point subs
- Insert/deletions
- Duplications)
Marfan syndrome
Type
Caused by
Causes
Symptoms
Type = Pan-ethic auto DOM
Caused by = A FB1 (fibrillin) mutation on X.15q
Causes= DOM negative pathogenesis
A Connective tissue disorder by altering cysteine residue bonds to make defective microfibrils to fuck up protein folding & stimulate premature proteolysis of extracellular normal microfibrils
Symptoms=
- Tall
- Arachbodactyly
- thoracolumbar scoliosis
- thoracic lordosis
- pectus
- excavatum joint laxity (hyperflexible joints)
- narrow palate
- ectopia lentitis (sup lens dislocation)
- myopia, cataracts, retinal detachment
- aortic dilation, regurg, MVP, aneurysms
Myotonic Dystrophy 1
VS
Myotonic dystrophy 2
1: Auto DOM disorder gets worse the more it’s passed on (anticipation)
A dynamic mutation from CTG repeats in the 3’ UTR of the DMPK gene at X.19q13.3 (instructions for making myotonic dystrophy protein kinase)
Symptoms =
- weakness + wasting
-Myotonic
- prolonged muscle contractions
- cataracts
- cardiac conduction defects
2: Auto DOM due to a tetranucleotide repeat in intron 1 of the CNBO (ZNF9) gene at X.3q21.3 (have 75-11,000 repeats)
Autosomal recessive (typically a loss of function gene)
2 heterozygotes = 1/4 unaffected, 2/4 carriers, 1/4 affected
1 hetero + 1 homo= 1/2 carriers & 1/2 affected
Equal frequency in both sexes & recurrence risk is 1/4
Ex. CFTR, Sickle cell, PKU
Cystic fibrosis
Type
Caused by
Causes
Symptoms
Mutation Heterogeneity
Type = Auto REC
Caused by =
- A mutation in CFTR protein on X.7q (allelic heterogeneity)
Causes =
- A 3bp deletion causing loss of Phe residues in CFTR proteins impairing their functions (messes with chloride channels on ciliated cells reducing motility)
Symptoms = Pleotropic
- Chronic lung infections & secondary cardiac
failure
- Sterility (males)
- Pancreas dysfunction (malabsorption +
steatorrhea)
- Osteoporosis/Arthritis/ Hypertrophic pulmonary
osteoarthropathy
- Cirrhosis/Gallstones/Hepatic stenosis
- Excessively salty sweat
Mutation Allelic Heterogeneity=
- Phe508del mutation (most common)
- Missense
- Frameshift
- Splicing error
- Nonsense
- Deletion
Sickle cell
Type
Caused by
Causes
Symptoms
Epidemiology
Type = Auto REC
Caused by =
- A missense mutation of B-globin’s genes at X.11p that subs glutamic acid with valine (pleiotropic)
Causes =
Changes normal HbA (hemoglobin A) to HbC via subbing glutamic acid for lysine at the 6th AA
* People with 1 HbC are carriers (no
symptoms but can pass sickle cell)
* People with 2 HbC have hemoglobin C
disease (mild hemolytic anemia &
jaundice)
* People with 1 HbC & HbS (sickle cell) have
hemoglobin SC disease (more severe
than HbC but milder than sickle-cell
disease)
Ex. HbAC (Hemo C carrier) + HbAS (Sickle carrier)
Kid 1 =HbAC, Kid 2 = HbAS, Kid 3 = HbSC (compound heterozygote), Kid 4 = HbAA (not affected)
Symptoms= Pleiotropic
- Sickle cell (anemia causes splenomegaly,
weakness, & bone defects)
(Ischaemia/thrombosis/infarction
cause abdominal/limb pain, spleen
infarction, rheumatism (bone pain),
osteomyelitis, hematuria, renal
failure, pneumonia, & heart failure)
Epi = African Americans
PKU (Phenylketonuria)
Type
Caused by
Causes
Symptoms
Mutation Heterogeneity
Type= Auto REC
Caused by =
- A mutated PAH gene (shows heterogeneity & pleiotropy)
Causes=
- Reduced phenylalanine hydroxylase (leading to a build-up of phenylalanine in body fluids)
Symptoms=
- Fair hair & skin (impaired melanin synthesis)
- Intellectual disability (most common)
- Musty/mousey odour
- Epilepsy (~50%)
- Extrapyramidal manifestations “DIG FAST”
* Distractibility, Indiscretion, Grandiosity,
Flighting ideas, Activity increase, Sleep Def,
& Talkative
Mutation Heterogeneity = In all 13 exons of PAH
- Missense (62%)
- Small/large deletions (13%)
- Splicing errors (11%)
- Silent (6%)
- Nonsense (5%)
- Insertions (2%)
Fatty Acid Synthesis Pathway & B-oxidation (7 rounds)
Excess glucose is converted to Pyruvate (from glycolysis), which uses the carnitine shuttle to enter the mitochondria
—> Pyruvate converts to Acetyl-CoA (PDH) & OAA (PDC+Biotin B6) in the mitochondria
—> Acetyl-CoA & OAA turn into Citrate
—> Citrate exits mito via citrate shuttle
—> Citrate makes OAA & Acetyl-CoA (ATP Citrate Lyase)
—> OAA turns to Malate & Malate to Pyruvate via Malic acid generating (NADP –> NADPH)
—> Acetyl-CoA uses CO2 to Malonyl-CoA (Acetyl-CoA Carboxylase+Biotin B6**)
—> Malonyl-CoA uses NADPH to turn into Palmitate (Fatty acid)
Insulin/Citrate/ATP/High glucose (+)
Glucagon/palmitoyl-acid/Acyl-CoA/Epinephrine/AMP/Catecholamines (-)
In: 8 Acetyl-CoA, 7 ATP, 14 NADPH
Out: 1 Palmitate (16C Long chain 14-20) & 7 H2O
CoFactors: CO2, NADPH, Biotin,
Essential Fatty acids include
Omega 6 (1)
Omega 3 (3)
6: Linoleic acid
3: alpha linoleic acid, Eicosapentaenoic acid, Docosahexaenoic acid
ALA, EPA, DHA
Saturated vs unsaturated
Saturated: No double bonds (c=c)
Unsaturated: 1 Double bond (c=c)
Polyunsaturated: Many double bonds (c=c)
Carnitine Shuttle (Fasted)
Fatty acids +CoA/ATP convert to fatty-Acetyl-CoA to enter the outer mito membrane (via Fatty Acetyl-CoA synthase)
—> Fatty Acetyl-CoA turns into Fatty Acetyl-Carnitine (CAT1 (Carnitine Acetyl TR1)
—> Fatty Acetyl-Carnitine enters the mito-matrix via the Carnitine transporter & uses CAT-2 (Carnitine Acetyl TR2) to dissociate into Fatty Acetyl-CoA & Carnitine (goes back to shuttle)
—> Fatty Acetyl-CoA uses NAD & FAD from the ETC to power its transformation into Acetyl-CoA (Fatty Acetyl-CoA DH med/long chains)
—> then Acetyl-CoA goes into the TCA, Ketone body production in the liver, & stimulates gluconeogenesis
Inhibitor: Malonyl (blocks CAT1) (product of FA Synthesis)
BALANCE ATP FOR B-OX WITH any saturated FA (even carbon #s):
4ATP x [n/2-1] +10ATP x [n/2] -2ATP
n= carbon # in FA
Diseases ass. with the carnitine shuttle
(Familial Lipidemia)
Primary Systemic Carnitine Def
“Her SCALDed Cat LicKs Fatty Veal & Venison”
Primary Systemic Carnitne def:
- Hypoketonia
- Hypoglycemia
- Hyperammonemia
- Vomit, coma, & death
- Fatty Liver
- AVOID fasting
- Treat with med/short chain FA diet
Fatty acid lengths
short/medium
long
very long
s/med: 2-12 (diffuse freely)
Long: 12-20 (use the Carnitine Shuttle)
very long: 20+ (oxidized in peroxisomes)
Fatty acid synthesis (Fed State)
Location
Cytosol/Liver
Fat tissue
Lactating mammary glands
Metabolism of chylomicrons (Fed State) pathway Eat —> Liver
Ingested fats get to the small intestine—> They’re formed into Nascent chylomicrons (coat: ApoB48 + PLs & core: TAG/CE/Lipid vitamins)
—> Chylomicrons enter the lymph then the blood
—> Chylomicrons mature in blood via HDL “Chylomicrons TG (coat: ApoB48+ApoCII+ApoE+PLs, core: TAG/CE/Lipid vitamins)
—> Chylomicron TG gets broken down to FA+Glycerol & Remnants
—> FA goes to the muscle (makes CO2+H2O) & Fat (TG stores)
—> Glycerol goes to liver
—> Chylomicron remnants (ApoB48+ApoE) go to ApoE receptors on the liver
—> Remnants are broken down via LDL endocytosis to get FA, Cholesterol, AA, & glycerol
Lipid/TAG synthesis (aka lipogenesis fed + insulin)
Glucose can go via the liver or straight to fat from the blood:
Glucose goes into the liver (via GLUT2) & converts to DHAP
—> DHAP turns into G3P (G3PDH)
—> Insulin triggers G3P to use 3FA CoA to make TG
—> TG then forms VLDL, which leaves the liver & either turn into glycerol (liver) or enters fat as 3FA-CoA
Glucose goes to fat (GLUT4) & converts into DHAP
—> DHAP turns into G3P (G3PDH)
—> G3P uses the 3FA-CoA (from the liver) in TG
Note: Hepatocytes use glycerol kinase to keep TAG synthesis independent of the glucose entry into the liver
Fat gets TAGs delivered as Chylomicrons (blood) & VLDL (liver)
Fat tissue puts TAGs into storage via
- HDL distributes:
Chylomicrons+B48+ApoCII+ApoE (blood)
&
VLDL+B-100+ApoCII+ApoE (liver)
- LPL activates (via APOCII) from free fatty acids & glycerol from Chylomicron Remnant (B48+ApoE) & VLDL Remnant (B100+ApoE)
—> Glycerol (goes to the liver to fuel G3P via glycerol kinase)
—> Free fatty acids move into fat via lipoprotein lipase (+Insulin induced) to supply 3FA-CoA (along with those from the liver to help G3P conversion to TGL
Lipolysis (Fasted state)
In fat tissue:
Low insulin & high epi/cortisol trigger
—> TGLs to form glycerol & fatty acids
—> Glycerol enters the liver (GLUT2) via glycerol kinase & enters gluconeogenesis (inhibited by high glucagon/cortisol)
—> Fatty acids move as Fatty acids albumins & free Short-chain-FA’s through the blood to enter the liver
—> They combine as fatty acids (liver) & do B-oxidation to form Acetyl-CoA
—> Acetyl-CoA enters the citric acid cycle & forms ketone bodies (ketogenesis)
—> Ketone bodies go to the brain
Fasting triggers
Lipolysis —> B-oxidation —> Acetyl-CoA
—> Ketogenesis = causing KETOACIDOSIS
Regulation of B-oxidation
Fed VS Fasted
“Feed Her BIG MACs” fed
fasted is opposite
Fed: high
- insulin/glucagon ratio
- Acetyl-CoA Carboxylation
- Malonyl
- Less Beta-Oxidation
Fasted: Low
- insulin/glucagon ratio
- Acetyl-CoA Carboxylation
- Malonyl
- More Beta-Oxidation
Diseases ass. with the carnitine shuttle
(Familial Lipidemia)
CAT1/CPT-I def
“1 CAt FeuLs with Nice Krispy Fats”
CAT1/CPT-I def: Affects liver
- Fasting hypoglycemia
- Hypoketosis
- Fatty liver
- Normal Carnitine
- Avoid fasting,
- Eat CHO, low-fat diets with med/short-chain FAs
Diseases ass. with the carnitine shuttle
(Familial Lipidemia)
CAT2 (Myopathic)
CAT2 (Myopathic): High fat stored in muscle
- Myoglobinuria
- Weak & hypotonic muscles
- Normal lactate
- TAG droplets in muscles
- Trigger is prolonged exercise/fasting
- Eat CHO & low-fat diet before exercise
Diseases ass. with the carnitine shuttle
(Familial Lipidemia)
MCAD def:
“MCADDSIDS HHAA”
MCAD def:
“MCADDSIDS HHAA”
- Decarboxylic metabolic (acidosis)
- SIDSS, vomit, coma
- Hypoglycemia
- Hypoketonia
- Hyperammonemia
Diseases ass. with the carnitine shuttle
(Familial Lipidemia)
Fatty Acetyl-CoA DehydrogenaseH deficiency
FAC-DH: Can’t convert it to Acetyl-CoA (no ketones & reduced TCA)
-Non-Ketonic hypoglycemia
- Hyperammonemia
Rx: Avoid fasting!!!
Ketone Metabolism (Ketogenesis)
Liver —> other tissues
Ketogenesis only happens in the liver to make acetoacetate
In the liver:
FA-CoA undergoes B-oxidation to turn into Acetyl-CoA
—> Acetyl-CoA converts to HMG-CoA (via HMG-CoA Synthase**)
—> HMG-CoA then turns into Acetoacetate (HMG-CoA lyase)
—> Acetoacetate can go directly to other tissues or turn into acetone (goes to cytoplasm) or 3-hydroxybutyrate (via NADP to NAD)
—> Acetone yeets into the cytoplasm (Build-up causes fruity-smelling breast & indicates ketoacidosis)
In the mito-matrix:
—> 3-Hydroxybutyrate turns back into acetoacetate once it gets to non-hepatic tissue (NAD to NADP)
—> Acetoacetate turns into Acetoacetyl-CoA (via succinyl-CoA acetoacetate TR)
—> Acetoacetyl-CoA then splits into 2 Acetyl-CoA to enter the TCA
Ketoacidosis can be due to 2 main things:
Diabetes Mellitus Type 1
&
Prolonged fasting
Ketone body types:
Primary
Secondary
Neutral
P: Acetoacetate
S: 3/B-Hydroxybutyrate
N: Acetone (excreted via lungs = fruity smell)
Fuels of Organs in FED vs FASTED + STARVED
Brain
Heart
Liver
Muscle
RBC
Brain:
-Glucose (FED+FAST)
- Ketones (STARVED)
Heart:
- Glucose (FED+FAST)
- Ketones (STARVED)
Muscle:
- Glucose (FED)
- Fatty acid (FAST)
- Fatty acid/ketones (STARVED)
Liver:
- Glucose (FED)
- Fatty acid (FAST)
- AA (STARVED)
RBCs:
- Glucose (FED+FAST+STARVED)
Cholesterol vs. Ketone synthesis
Cholesterol:
- Cytoplasm/SER
- HMG CoA intermediate
- Cyto-HMG CoA synthase
- HMG CoA reductase (rate-limiting step)
&
Ketones
- Mitochondria
- HMG-CoA intermediate
- Mito-HMG-CoA synthase (regulatory step)
- HMG-CoA Lyase
Cholesterol synthesis pathway (Fed + Insulin)
Mostly happens in the liver, adrenal cortex, testes, ovaries, & intestines
—> 2 Acetyl-CoA’s combine to form Acetoacetyl-CoA (4C) (via Thiolase)
—> Acetoacetyl-CoA (4C) combines with another Acetyl-CoA to make HMG-CoA (6C) (via HMG-CoA Synthase)
—> HMG-CoA enters ER & turns into Mevalonate (6C) (via HMG-CoA reductase**)
—> Mevalonate (6C) turns into Isoprenoid unit (5C)
—> Isoprenoid unit (5C) combines with another to form Geranyl PPi (10C)
—> Geranyl forms Farnesyl PPi (15C)
—> Farnesyl PPi (15C) combines with another Farnesyl (15C) to make Squalene (30C)
—> Squalene becomes Lanosterol (30C) which finally becomes Cholesterol (27C)
Regulation of cholesterol synthesis
Rate limiting enzyme:
Feedback
Hormonal/non-covalent mod
RLE: HMG-CoA Reductase
F: Cholesterol inhibits HMG-CoA Red via SREBP (Sterol-Regulatory-Element-Binding-Protein)
H:
- Dephosphorylation (+)
- Insulin & Thyroxine (+)
- Glucagon & Glucocorticoids (-)
Specialized products of cholesterol synthesis include 4 things
Bile salts
Vitamin D
Sex hormones
Corticosteroids
The General Fates of Cholesterol
- Most are turned into bile salts
- pooped out as cholestanol & coprostanol (it can’t be degraded or make energy)
- Precursor for vitamin D, sex hormones, & corticosteroids
Odd Chain fatty acid oxidation metabolism
AA’s
Pathway
AA: Methionine, Isoleucine, Valine, & Threonine
Pathway
—> AA’s form Propionyl-CoA & are turned Propionyl Carnitine (yeet) + Methylmalonyl-CoA (via propionyl CoA Carboxylase (PCC) with Biotin (B6) & ABC-enzyme)
—> Methylmalonyl-CoA forms succinyl-CoA (via Methylmalonyl-CoA Mutase with Vit B12/Cobalamin)
—> Succinyl-CoA then enters the TCA
Odd Chain fatty oxidation disease:
Propionyl-CoA carboxylase def
“props to the VILlIAn, ACDc!”
- Elevated propionyl-CoA products (Propionyl carnitine & propionic acid)
- Inhibits urea cycle (hyperammonemia)
- Acidosis
- Vomit, Lethargy, Irritability, CNS issues, Coma, & Death
Sphingolipidosis:
Nieman Picks (Jews)
“Nieman SHot FuN Cocks”
AR disorder due to def sphingomyelinase
- Progressive neuronal degeneration
- Cherry red macula spot
- Hepatosplenomegaly
- Foam cells
- build up of sphingomyelin
Sphingolipidosis:
Tay-Sachs (Jews)
“Tay LOved Her Hands, He Cares & says GM”
Def Hexosaminidase A :
- Lysosomes with onion skin
- Hyperreflexia
- Hyperacusis
- Cherry red macula spot
- Build up of GM2 gangliosides
Sphingolipidosis:
Sandhoff disease
Def Hexosaminidase A & B
Sphingolipidosis:
Krabbe disease:
“KRABby Patty’s Dam Good”
Def B-Galactosidase:
- Retardation (developmental delay)
- Optic ATROPHY
- Peripheral neuropathy
- Destroyed oligodendrocytes
- Builds up Glucocerebroside
Sphingolipidosis:
Gaucher disease
“GaucHer GaNGs uP on bone”
Def B-Glucosidase:
- Hepatosplenomegaly
- Gaucher cells
- Necrosis of bone (femur)
- Build up of Glucocerebride
- Pancytopenia
Sphingolipidosis:
Fabry disease;
“FAbry’s CHAPteR”
Def Alpha-galactosidase:
- Peripheral neuropathy
- Hypohidrosis
- Angiokeratomas
- Renal & cardiovascular failure
- Build up Ceramide trihexoside
Sphingolipidosis:
Metachromatic Leukodystrophy
“MetAChromAtic Penile DilDos”
Def Arylsulfatase A:
- Central & Peripheral demyelination
- Ataxia
- Dementia
- Build up of cerebroside sulfate
Lipoproteins:
Chylomicrons (transport)
VLDL (transport)
IDL (transport)
HDL (transport)
Chylo: moves TAGs from tummy to tissues & has ApoB48,CII, & E
VLDL: moves TGs from liver to tissues & has ApoB100, CII, & E
IDL: Remnant of VLDL it moves cholesterol into cells & has ApoB100
HDL: picks up cholesterol in the blood & brings it to the liver & steroidogenic tissues with SR-B1 receptors it has ApoD (Shuttles Apo CII & E through blood)
Lipoprotein receptors
ApoE-R (remnant)
LDL-R
SR-A1
SR-B1
ApoE-R: ApoE (IDL & CM)
LDL-R: ApoB100 (LDL cholesterol via liver + tissues) REG VIA CHOLESTEROL
SR-A1: uptake oxLDL-cholesterol via macrophages
SR-B1: uptake HDL + CE via liver
Dyslipoproteinemia:
Type 1 (Hyperchylomicronemia/hypertriglyceridemia)
“1 LAP, 2 CHAMpions an eXciting FinaL”
Def LDL:
- low ApoCII
- Hepatosplenomegaly
- Milky plasma
- Xanthomas
- Fatty liver
- Abdominal pain post meal
- Lipemia retinalis
VLDL, LDL, HDL levels are normal
- F
Dyslipoproteinemia:
Type IIa (Familial hypercholesterolemia, FH) AD
“2 ReaL RACers Fly Clear Through the eXit”
Def LDL-receptor:
- Risk of atherosclerosis & coronary artery disease
- Tendon Xanthomas
- Corneal Arcus
High LDL & HDL
Normal VLDL
Dyslipoproteinemia:
Type 3 (Dysbetalipoproteinemia) AR
“3 EAters Hurry Home eXcited for RAmen”
Def ApoE:
- Hypercholesterolism
- Hypertriglyceridemia
- Xanthomas (Tubular erruptive)
- high Remnants (IDL & CM levels)
- risk of Atheromatous vascular disease
Dyslipoproteinemia:
Abetalipoproteinemia
“ABet My Last DollAR He’s skinny”
Def MTTP:
- No ApoB formation
- poor fat soluble vitamin absorption
- Low LDL, VLDL, Cholesterol, CM, & TAGs
- NORMAL HDL
- Retinitis pigmentosum
- Myopathy
- Hemolytic anemia
- Degenerated dorsal column
- Acanthocytes (spiney RBCs)
14
Patients with elevated serum LDL levels (>120 mg/dL) are first encouraged to reduce these levels through a combination of diet and exercise. If this fails, they are often prescribed statins. The key for statin treatment reducing circulating cholesterol levels is which one of the following?
A. Increased activity of CETP
B. Upregulation of LDL receptors
C. Reduced synthesis of HDL
D. Reduced synthesis of chylomicrons
E. Increased activity of LPL
B. Upregulation of LDL receptors
15
Laboratory studies shown that deficiency of folic acid markedly decreases formation of proerythroblasts in the bone marrow. Subsequently, many of these erythroid precursor cells undergo apoptosis without further maturation. Deficiency of which of the following would explain cell apoptosis in these experiments?
A. Pyridoxine
B. Cobalamin
C. Thymidine
D. Homocysteine
E. Cytosine
C. Thymidine
16
Ectrodactyly is an autosomal dominant trait that causes missing middle fingers (lobster claw malformation). A grandfather and grandson both have ectrodactyly, but the intervening father has normal hands by x-ray. Which of the following terms applies this family?
A. New mutation
B. Incomplete penetrance
C. Anticipation
D. Variable expressivity
E. Germinal mosaicism
B. Incomplete penetrance
A 5-year-d boy (III-1) of Turkish descent is brought to the physician because of yellowness of his eyes. The patient’s mother explained that this appeared after taking a long-term antibiotic that the physician prescribed for his severe chest infection. The physician performed a detailed analysis of his family (pedigree seen below) that includes relatives that have become ill when given the same antibiotic. Which of the following is the most likely diagnosis?
A. Neurofibromatosis
B. Glucose-6-phosphate dehydrogenase deficiency
C. Tay Sachs disease
D. Sickle cell disease
E. Leber hereditary optic neuropathy
B. Glucose-6-phosphate dehydrogenase deficiency
18
A couple presents for genetic counseling after their first child (a son) is born with achondroplasia, a dwarfing syndrome. The physician obtains the following family history: the husband (George) is the first-born of four male children, and George’s next-oldest brother has cystic fibrosis. The wife is an only child, but she had DNA screening because a second cousin had cystic fibrosis and she knows that she is a carrier. There are no other medical hereditary problems in the couple or their families. The physician draws the pedigree with the female member of the couple on the left. The generations are numbered with Roman numerals and individuals with Arabic numerals; individuals affected with achondroplasia or cystic fibrosis are indicated. Which of the following risk figures applies to the next child (Ill2) born to George and his wife?
A. Achondroplasia virtually 0, cystic fibrosis 1/4
B. Achondroplasia 1/2, cystic fibrosis 1/8
C. Achondroplasia virtually 0, cystic fibrosis 1/8
D. Achondroplasia virtually 0, cystic fibrosis 1/6
E. Achondroplasia 1/2, cystic fibrosis 1/4
D. Achondroplasia virtually 0, cystic fibrosis 1/6
19
A 3-month-old male is found to have some neurological abnormalities on routine check-up. Comprehensive laboratory evaluations reveal impaired tetrahydrobiopterin synthesis. Which of the following compounds is most likely deficient in this patient?
A. Acetylcholine
B. Melanin
C. GABA
D. Histamine
E. Dopamine
E. Dopamine
A 6-month-old male patient with a 2-month history of persistent cough was treated with various antibiotics but showed no improvement. He was subsequently admitted to Children’s Hospital with respiratory distress, pneumonia with extensive bilateral pulmonary infiltrates, and impending respiratory failure of unknown etiology. Laboratory test indicated a deficiency of _________in the serum:
A. Xanthine oxidase
B. Adenosine deaminase
C. UMP synthase
D. Ribonucleotide reductase
E. Carbamoyl phosphate synthetase
B. Adenosine deaminase
Allopurinol can be used to treat gout because of its ability to inhibit which of the following reactions?
Select one:
A. Xanthine to uric acid
B. IMP to Inosine
C. Guanosine to GMP
D. Inosine to hypoxanthine
E. AMP to IMP
A. Xanthine to uric acid
22
A newborn becomes progressively lethargic after feeding and increases his respiratory rate. He becomes virtually comatose, responding only to painful stimuli, and exhibits mild respiratory alkalosis. Suspicion of a urea cycle disorder is aroused, and evaluation of serum amino acid levels is initiated. If the patient has argininosuccinate synthetase deficiency, the level of which of the following amino acids is increased?
A. Orotic acid
B. Citrulline
C. Arginine
D. Glycine
E. Ornithine
B. Citrulline
23
A 2-year old boy is exhibiting developmental delay and has started to bite his lips and fingers. Orange-colored “sand” is found in his diapers. The child has an inability to metabolize which of the following molecules?
A. Adenine
B. Glycine
C. Hypoxanthine
D. Thymine
E. Uric acid- had this previously
C. Hypoxanthine
24
A 42-year old man comes to the office due to numbness and tingling in both legs and difficulty walking for the past several months. He has also noticed that tires more easily with physical activity. Physical examination shows conjunctival pallor and loss of vibration and position sensation in the bilateral lower extremities with associated gait ataxia. The reminder on the examination is within the normal limits. Blood tests reveal Hb is 10 mg/L, MCV is 110 fl with hypersegmented neutrophils. Which of the following findings is most likely to be present upon further questioning of the patient? Vit b-12 deficiency
A. Strict vegan diet for the past 6 months
B. Use a phenytoin drug for the past 3 months
C. Total gastrectomy 3 years ago
D. Ongoing treatment for latent tuberculosis
E. Working on the battery recycling factory
C. Total gastrectomy 3 years ago
25
The question is based on the following diagram that represents the utilization of amino acids:
What does Y represent?
A. Fumarate
B. Malate
C. Citrate
D. Succinyl COA (E9)
E. Cysteine
D. Succinyl COA (E9)
14
Patients with elevated serum LDL levels (>120 mg/dL) are first encouraged to reduce these levels through a combination of diet and exercise. If this fails, they are often prescribed statins. The key for statin treatment reducing circulating cholesterol levels is which one of the following?
A. Increased activity of CETP
B. Upregulation of LDL receptors
C. Reduced synthesis of HDL
D. Reduced synthesis of chylomicrons
E. Increased activity of LPL
B. Upregulation of LDL receptors
13
The urea cycle is the major mechanism in the human body for removal of nitrogen. Which statement correctly describes steps of the urea cycle?
A. Citrulline is exchanged for ornithine across the mitochondrial membrane
B. Ornithine is generated in the mitochondria
C. Two ATPs are used for one complete cycle
D. Citrulline is synthesized in the cytosol
E. Citrulline initiates and is regenerated by the cycle
A. Citrulline is exchanged for ornithine across the mitochondrial membrane
12
A 10-year old boy develops convulsions. After running an Electroencephalogram (EEG), a neurologist determines than the child has epilepsy. He is started on benzodiazepine, which promotes the activity of GABA. GABA is derived from:
A. Glutamate
B. Ornithine
C. Glycine
D. Tyrosine
E. Glutamine
A. Glutamate
11
A premature infant is born to 35-year old female. He has respiratory difficulties and is placed on mechanical ventilation. Glutamate is newly synthesized in this infant’s liver _____ to oxidative deamination. Which of the following is the cofactor of this reaction?
A. TPP
B. FAD+
C. NAD+
D. PLP
E. THB
F.THF
C. NAD+
A pedigree is shown of a couple with African American and Mediterranean ancestry. Two of their grandchildren have sickle cell disease. They both have had numerous hospital admission from infancy. IV-1 has been diagnosed with hand and foot syndrome, leg ulcers and aplastic crisis due to parvovirus B-19 infection while IV-2 has had acute chest syndrome, splenic sequestration, and priapism (a sustained, painful, and unwanted erection). What is the probability that individual II-5 is homozygous normal?
A. 2/3
B.0
C. 1/4
D. 1/2
E. 1/3
D. 1/2
9
A 3-day-old female infant presents with poor feeding, lethargy, vomiting after feeding, and seizures. Labs revealed ketoacidosis and elevated hydroxypropionic acid levels. Upon administration of parenteral glucose and protein-restricted diet the infant began to recover. Which of the following diet is most likely recommended for this infant?
A. Low-tryptophan diet
B. Low-phenylalanine diet
C. Low-leucine diet
D. Low-cysteine diet
E. Low-valine diet
E. Low-valine diet
8
A 32-year-old man comes to the office due to skin lesions on his palms. The patient has yellowish skin nodules over the palmar creases that have been increasing in size and number over the past several years. He also has small clusters of yellow papules on his elbows, knees, and buttocks. His father died of a myocardial infarction age 56. Biopsy of his lesions shows accumulation of lipid-laden macrophages. Immunoblot analysis suggests a lack of Apo3 and ApoE4 in his circulating lipoproteins. Which of the following is most likely impaired in this patient?
A. Apolipoprotein C-Il production
B. Lipoprotein lipase activity
C. Chylomicron remnant uptake by liver cells
D. Cholesterol esterification on the blood
E. LDL uptake by hepatocytes
E. LDL uptake by hepatocytes
7
A missense mutation occurs in the gene encoding for the enzyme cystathionine beta-synthase. This mutation causes a various phenotypic manifestation including skeletal deformities, mental retardation and vascular thromboses. Which of the following best describes this phenomenon?
A. Imprinting
B. Variable penetrance
C. Polyploidy
D. Segregation
E. Pleiotropy
E. Pleiotropy
6
The family just immigrated from the Guatemala. They brought a 3-year-old son to care unit with concerns about respiratory infection. On physical examination you found that patient is suffering from severe mental retardation and seizures, and he has fair skin and hair. A few days later he dies from an overwhelming respiratory infection. You suppose that brain can be affected and order a brain autopsy. The analysis shows pallor of the substantia nigra, the locus coeruleus, and the vagal nucleus dorsalis. A deficiency of which of the following enzymes is most likely in this patient?
A. Methionine synthase
B. Tyrosinase
C. Homogentisic acid oxidase
D. Branched chain ketoacid dehydrogenase
E. Phenylalanine hydroxylase
E. Phenylalanine hydroxylase
5
A researcher in Merck wants to develop a method of labeling pyrimidine with 15N and 12C for use in future spectroscopic studies. Pyrimidine synthesis will be done in a test tube using only the enzymes necessary for de novo pathway. Which starting materials should be labeled with the heavy nitrogen and carbon in order to maximize 15 N and 12C incorporation into pyrimidines?
A. Aspartate, glycine, glutamine and formyl-THF
B. Asparagine, alanine, and glutamine and formyl-THF
C. Asparagine, glycine, glutamine and methylene-THF (purine- with asparate)
D. Aspartate, glutamine and methylene-THF
E. Aspartate, glutamate and methylene-THF
D. Aspartate, glutamine and methylene-THF
4
A 43-year-old female presents to the office for fatigue. Although she had it for several months, over the past few weeks, her fatigue has been worsening. She has no symptoms. He denies any changes in her bowel habit or blood in her stool. There has been no change in her mood or difficulty with her sleep. She was recently fired from her job as she was found to come to work drunk several times. She says that she can quit everything but not alcohol. Her diet is poor. The physical exam reveals a malnourished lady with moderate conjunctival pallor. The lab results are Hemoglobin 10 g/dL, with MCV of 108 fl. Elevated level of which of the following will be most likely to be found in this patient?
A. Methylmalonic acid only
B. Methionine only
C. Methylmalonic acid + homocysteine
D. Homocysteine only
E. Methionine + homocysteine
D. Homocysteine only
3
A 2-year-old male brought to your office by her mother with complains that her son did not start speaking. On physical examination the patient is at the 10th percentile for height and 5th percentile for weight. Her skin is pale, and she is lethargic. Blood tests reveal Hb is 5.0 mg/L, MCV is 105 fl with hypersegmented neutrophils. Urinalysis is negative for glucose but shows very high levels of orotic acid. Which of the following explains patient’s anemia?
Select one:
A. Deficiency of pyruvate kinase
B. Deficiency of UMP synthase
C. Deficiency of cobalamin
D. Deficiency of folic acid
E. Deficiency of OTC
B. Deficiency of UMP synthase
2
The question is based on the following diagram that represents the utilization of amino acids:
What is the cofactor for enzyme E3?
A. THB
B. Biotin
C. Methyl-cobalamin
D. PLP
E. Methyl-THF
D. PLP
1
A 5-year-old boy with developmental delay is brought to the office due to difficulty “seeing the board” at school. Examination shows a boy with a tall, thin habitus with elongated limbs. Fundoscopy shows bilateral lens subluxation. Four years later the patient was found with cerebral artery thrombosis and old renal infarcts. His parents wish to know if anything should be done for preventing his problems. Which of the following is the most appropriate for this patient?
Select one:
A. Low methionine diet with pyridoxine supplementation
B. Low cysteine diet with folic acid supplementation
C. Low isoleucine with thiamine supplementation
D. Low tyrosine diet with tetrahydrobiopterin supplementation
E. Low phenylalanine diet with tyrosine supplementation
A. Low methionine diet with pyridoxine supplementation
Urea cycle steps
In the hepatic mito:
- Ammonia + co form Carbamoyl phosphate (via Carbamoyl Phosphate Synthetase I***)
—> Carbamoyl +Ornithine combine to form citrullin via (ornithine transcarbamylase)
In hepatic cyto:
—> Citrulline + aspartate + ATP combine to form Argininosuccinate (via argininocuccinate synthase)
—> Argininocuccinate forms arginine & fumarate (via arginosuccinase)
—> arginine can turn into urea (excreted by kidney) or become ornithine to enter the cycle again
AA catabolism
Absorbed into intestine & moves into bloods
Transamination (Turns AA to glutamate)
- AA to keto acid (aminoTR)
Deamination (Glutamate to ammonia)
- Glutamate to A imminoglutarate (glutamate DH)
- Immunoglutarate to ammonia
Urea cycle
—> ammonia to urea
urea cycle def
Carbamoyl phosphate def
Ornithine Transcarbomylase def: X-linked
—> Build up carbomyl phosphate & converts it to toxic Orotic acid
- low citrulline
- high carbamoyl phosphate & Orotic acid conversion
- Trapped ammonia in tissues (hyperammonemia: Asterixis (neg myoclonus) & cerebral edema
Rx: reduce dietary proteins or decrease ammonia (lactulose or Rifaximin)
Eicosanoids (local/tissue hormones)
made within tissue via arachidonic acid (Phospholipase A2) cleaves
- Prostaglandins (H2) (cylooxygenase) (mediates pain/inflammatory response/vasodialtion/stim uterine contraction/sperm motility)
- Thromboxanes (H2) (vasoconstriction platelet aggregation
- Leukotrienes (A4) (lipoxygenase) (chemotaxis/bronchoconstriction)
-Prostacycline: antagonist (vasodilation & reduce platelet aggregation)
